Asthma Trials Research Articles

Lessons learned from clinical trials of asthma.

Exacerbations of persistent or intermittent asthma should be anticipated by physicians and health-care professionals. Patients who are likely to experience an exacerbation often have a history of an exacerbation in the previous year, and the absolute eosinophil count in peripheral blood is ≥ 400/μL. Similarly, expectorated or induced sputum eosinophilia of ≥2% is associated with exacerbations. These phenotypic findings have led to effective biologic therapies, which target eosinophils or immunoglobulin E or the T-helper type 2 phenotype, especially in children, adolescents, and adults with frequent exacerbations. In children, a reduced forced expiratory volume in the first second of expiration (FEV1) to forced vital capacity ratio can be associated with future exacerbations, although the FEV1 may be in the normal range, even with children who have persistent severe asthma. Asthma control questionnaires did not differentiate between children with or children without a future exacerbation. Alternatively, in adults, the lower baseline FEV1 (2.3 L [74% predicted] versus 2.5 L [78% predicted]) identified patients more likely to have a future exacerbation compared with patients who were not having an exacerbation. After correcting for FEV1, the asthma control questionnaire data were associated with exacerbations. In adolescents (ages ≥ 12 years) and adults with persistent mild asthma, most (73%) did not have sputum eosinophilia, and some of these patients responded well to the anticholinergic, tiotropium, which would argue differently from administration of an inhaled corticosteroid as first-line controller therapy. In a three-track study of patients with persistent mild asthma, as-needed budesonide-formoterol and scheduled budesonide were associated with approximately one-half of the annual exacerbation rate of as-needed albuterol. In patients with persistent moderate-to-severe asthma, tiotropium added to controller therapy caused an increase in FEV1 without improving the asthma control questionnaire findings. There were two studies that explored whether either quadrupling or quintupling the inhaled corticosteroid at the first sign of loss of control of asthma would provide meaningful reductions of severe exacerbations of asthma, but the findings did not support this strategy. Both biologic therapies and environmental control (dust mite impermeable encasings) have resulted in reductions of exacerbations in patients with persistent moderate and severe asthma.

Vitamin D3 therapy in patients with asthma complicated by sinonasal disease: Secondary analysis of the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma trial

Vitamin D3 therapy in patients with asthma complicated by sinonasal disease: Secondary analysis of the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma trial

A Patient-Centered Approach to Informed Consent: Results from a Survey and Randomized Trial.

Traditional informed consent documents tend to be too lengthy and technical to facilitate proper patient engagement. Patient-centered, short informed consent content could be equally informative, while minimizing patient burden and producing greater patient engagement. This study aimed to develop and evaluate patient-centered, patient-designed paper and video informed consent formats. Two studies were conducted. In study 1, 118 self-identifying asthma patients recruited from a national, online pool completed survey tasks from their personal computers. Participants in study 1 were randomly assigned to examine sections of a standard informed consent document for an asthma trial and to select information they deemed critical to their decision making. In study 2, a sample of 83 self-identifying asthma patients completed experimental tasks in a university laboratory. Participants in study 2 were randomly assigned to a full informed consent document; a shortened, patient-designed informed consent document created from study 1; or a video with content matched to the shortened paper form. Study 1 yielded a more readable, concise version of a standard informed consent document (5 v. 17 pages). This shortened, patient-designed form closely met normative criteria for good clinical practice. In study 2, participants who viewed either the shortened paper consent or video reported greater engagement than those viewing the standard paper consent, without lowered performance on any other decision-relevant variables (i.e., comprehension, judged risk/benefit, feelings of trust). The video consent format did not cause increased enrollment. Results suggest that providing concise informed consent content, systematically developed from patients' self-reported information needs, may be more effective at engaging and informing clinical trial participants than the traditional consent approach, without detriment to trial comprehension, risk assessment, or enrollment.

Saving in medical costs by achieving guideline-based asthma symptom control: a population-based study.

Asthma control is increasingly used as an outcome measure in asthma trials. Economic evaluations of asthma interventions require converting the impact of interventions on control to impact on resource use. The purpose of this study was to estimate the savings in direct costs by achieving asthma symptom control as defined in the Global Initiative for Asthma (GINA) 2014 management strategy. Adolescents and adults with asthma were recruited through random digit dialing. Asthma control per GINA and the use of healthcare resources were assessed at baseline and three-monthly visits up to 1 year. We used regression models to associate costs, measured in 2012 Canadian dollars ($), with symptom control, adjusting for potential confounding variables. The final sample included 517 individuals (average age 48.9, 65.8% female) with mostly mild-moderate asthma contributing 2033 follow-up visits. In 598 (29.4%), 809 (39.8%), and 626 (30.8%) of visits, asthma was symptomatically controlled, partially controlled, or uncontrolled, respectively. The average 3-month costs of asthma were $134.5. Of these, 20.5% were attributable to inpatient care, 47.8% to outpatient care, and 31.5% to medication. Compared to controlled asthma, partially controlled asthma was associated with a nonsignificant increase of $9.5 (95% CI -$13.6 - $32.6) in adjusted 3-month costs and uncontrolled asthma with a statistically significant increase of $81.7 (95% CI $48.5 - $114.9). A substantial fraction of this population-based sample of largely mild-moderate asthmatics was symptomatically uncontrolled. Achieving symptom control was associated with a reduction in direct costs. The adjusted values from this study can be used to inform cost-effectiveness analyses of asthma treatments.

Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children.

Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children.

Psychometric Properties of the Asthma Symptom Diary (ASD), a Diary for Use in Clinical Trials of Persistent Asthma

No currently available asthma symptom diary has sufficient validation to be recommended for use as a core asthma outcome measure. The objective of this study was to provide validation data for the 10-item asthma symptom diary (ASD). Data were collected in a 4-week prospective, observational study. Subjects completed 3 study visits, completing the ASD twice daily at home for 28 days. Psychometric properties in terms of dimensionality, reliability, validity, and responsiveness were assessed. Data from 276 subjects were analyzed; mean age was 42.9 (standard deviation [SD]= 16.4) years, mean asthma duration was 23.3 (SD= 16.8) years, and 69.6% were female. Confirmatory factor and Rasch analysis supported the ASD as unidimensional and adequately measuring the spectrum of asthma symptom severity. High Cronbach's α (0.94) and intraclass correlation coefficients (0.89-0.95) supported reliability. A high correlation between the 7-day average ASD score and the Asthma Control Questionnaire (ACQ) total score (r= 0.75) and Asthma Quality of Life Questionnaire total scores (r=-0.76), and a moderate correlation with FEV1% predicted (r=-0.30) supported convergent validity. Significant differences (P < .001) between groups classified by ACQ scores supported known-group validity. The 7-day average ASD scores were responsive to change, with significantly higher score changes (P < .001) in responders versus nonresponders. Minimally important differences were calculated and found to be in the range of 0.1-0.3. Results of this study indicated that the ASD is a reliable and valid asthma symptom measure for use in adult and adolescent asthma patients to evaluate the effect of treatment on asthma in clinical trials.

소아 천식 치료의 국외 보완대체의학 임상 연구 동향

Objectives : The purpose of this study is to analyze the trends in foreign clinical trials for pediatric asthma in complementary and alternative medicine (CAM). Methods : We reviewed 31 randomized controlled trials (RCT) for pediatric asthma treatment in CAM published from 2005 to 2015 in PubMed and analyzed their treatments, compounds of herbal medicines, acupoints, methods of assessment, and treatment results. Results : The treatments used in the studies were herbal medicines, acupuncture, acupoint application, breathing training, supplement, normocaloric diet, yoga, massage therapy, and art therapy. The frequently used herbs were Asari Herba Cum Radix (細辛). Ephedrae Herba (麻黃), Astragali Radix. The most common acupoints were Feishu (肺兪, BL13). The methods of assessment in pediatric asthma were symptom scale, questionnaire of Quality of Life, lung function test, laboratory studies, and medication usage. In 28 out of 31 studies, treatment group gets better than non-treated group. Conclusions : This study shows that CAM is effective in treating pediatric asthma. More clinical studies using objective outcome measures are needed to prove its efficacy clearly.

Diet and asthma: an update.

Our objective was to provide an overview and discussion of recent experimental studies, epidemiologic studies, and clinical trials of diet and asthma. We focus on dietary sources and vitamins with antioxidant properties [vitamins (A, C, and E), folate, and omega-3 and omega-6 polyunsaturated fatty acids (n-3 and n-6 PUFAs)]. Current evidence does not support the use of vitamin A, vitamin C, vitamin E, or PUFAs for the prevention or treatment of asthma or allergies. Current guidelines for prenatal use of folate to prevent neural tube defects should be followed, as there is no evidence of major effects of this practice on asthma or allergies. Consumption of a balanced diet that is rich in sources of antioxidants (e.g. fruits and vegetables) may be beneficial in the primary prevention of asthma. None of the vitamins or nutrients examined is consistently associated with asthma or allergies. In some cases, further studies of the effects of a vitamin or nutrient on specific asthma phenotypes (e.g. vitamin C to prevent viral-induced exacerbations) are warranted. Clinical trials of 'whole diet' interventions to prevent asthma are advisable on the basis of existing evidence.

Asthma exacerbations and lung function in patients with severe or difficult-to-treat asthma

Asthma exacerbations and lung function in patients with severe or difficult-to-treat asthma

Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment

The prostaglandin D2 (PGD2) receptor, CRTH2, plays a role in allergic airway inflammation. The efficacy of BI 671800, a CRTH2 antagonist, was assessed in 2 separate trials in patients with asthma, in either the absence or the presence of inhaled corticosteroid (ICS) therapy. In this study, BI 671800 (50, 200 or 400 mg) and fluticasone propionate (220 μg) all given twice daily (bid) were compared with bid placebo in symptomatic controller-naïve adults with asthma (Trial 1), and BI 671800 400 mg bid compared with montelukast 10 mg once daily (qd), and matching placebo bid, in patients with asthma receiving inhaled fluticasone (88 μg bid) (Trial 2). The primary endpoint in both trials was change from baseline in trough forced expiratory volume in 1 s (FEV1) percent predicted. After 6 weeks' treatment, adjusted mean treatment differences (SE) for the primary endpoint compared with placebo in Trial 1 were 3.08% (1.65%), 3.59% (1.60%) and 3.98% (1.64%) for BI 671800 50, 200 and 400 mg bid, respectively, and 8.62% (1.68%) for fluticasone 220 μg bid (p = 0.0311, p = 0.0126, p = 0.0078 and p < 0.0001, respectively). In Trial 2, adjusted mean FEV1 (SE) treatment differences compared with placebo were 3.87% (1.49%) for BI 671800 400 mg bid and 2.37% (1.57%) for montelukast (p = 0.0050 and p = 0.0657, respectively). These findings suggest that BI 671800 is associated with a small improvement in FEV1 in symptomatic controller-naïve asthma patients, and in patients on ICS.

Use of mobile devices and the internet for multimedia informed consent delivery and data entry in a pediatric asthma trial: Study design and rationale

IntroductionPhase III/IV clinical trials are expensive and time consuming and often suffer from poor enrollment and retention rates. Pediatric trials are particularly difficult because scheduling around the parent, participant and potentially other sibling schedules can be burdensome. We are evaluating using the internet and mobile devices to conduct the consent process and study visits in a streamlined pediatric asthma trial. Our hypothesis is that these study processes will be non-inferior and will be less expensive compared to a traditional pediatric asthma trial. Materials/methodsParents and participants, aged 12 through 17years, complete the informed consent process by viewing a multi-media website containing a consent video and study material in the streamlined trial. Participants are provided an iPad with WiFi and EasyOne spirometer for use during FaceTime visits and online twice daily symptom reporting during an 8-week run-in followed by a 12-week study period. Outcomes are compared with participants completing a similarly designed traditional trial comparing the same treatments within the same pediatric health-system. After 8weeks of open-label Advair 250/50 twice daily, participants in both trial types are randomized to Advair 250/50, Flovent 250, or Advair 100/50 given 1 inhalation twice daily. Study staff track time spent to determine study costs. ResultsParticipants have been enrolled in the streamlined and traditional trials and recruitment is ongoing. ConclusionsThis project will provide important information on both clinical and economic outcomes for a novel method of conducting clinical trials. The results will be broadly applicable to trials of other diseases.

Markers of Differential Response to Inhaled Corticosteroid Treatment Among Children with Mild Persistent Asthma

Inhaled corticosteroids are recommended as first-line therapy for children with mild persistent asthma; however, specific patient characteristics may modify the treatment response. Identify demographic, clinical, and atopic characteristics that may modify the inhaled corticosteroid treatment response among children enrolled in the Treating Children to Prevent Exacerbations of Asthma trial. Children aged 6 to 18 years with mild persistent asthma were randomized to 44 weeks of combined, daily, rescue, or placebo treatment. Daily treatment consisted of 40 μg of beclomethasone twice daily. Rescue treatment consisted of 40 μg of beclomethasone accompanying each symptom-driven albuterol actuation. Combined treatment consisted of both. Outcomes included time to first exacerbation and proportion of asthma control days. Fourteen baseline characteristics were selected for interaction testing on the basis of their clinical relevance. Two hundred eighty-eight children were randomized. Seventy-five percent were white, and 55% were male. As measured by time to first exacerbation, 4 characteristics identified children who received greater benefit from treatment: non-Hispanic ethnicity, positive aeroallergen skin test result, serum immunoglobulin E level of 350 K/μL or more, and history of oral corticosteroid use in the year before enrollment. As measured by asthma control days, 4 characteristics identified children who received greater benefit from treatment: male sex, positive aeroallergen skin test result, serum immunoglobulin E level of 350 K/μL or more, and incomplete run-in asthma control. Children with mild persistent asthma who have markers of atopic asthma or who have greater asthma burden may obtain greater benefit from beclomethasone therapy. Additional study is needed to confirm whether these markers can guide individualized therapy.

Using an electronic medical record (EMR) to conduct clinical trials: Salford Lung Study feasibility.

BackgroundReal-world data on the benefit/risk profile of medicines is needed, particularly in patients who are ineligible for randomised controlled trials conducted for registration purposes. This paper describes the methodology and source data verification which enables the conduct of pre-licensing clinical trials of COPD and asthma in the community using the electronic medical record (EMR), NorthWest EHealth linked database (NWEH-LDB) and alert systems.MethodsDual verification of extracts into NWEH-LDB was performed using two independent data sources (Salford Integrated Record [SIR] and Apollo database) from one primary care practice in Salford (N = 3504). A feasibility study was conducted to test the reliability of the NWEH-LDB to support longitudinal data analysis and pragmatic clinical trials in asthma and COPD. This involved a retrospective extraction of data from all registered practices in Salford to identify a cohort of patients with a diagnosis of asthma (aged ≥18) and/or COPD (aged ≥40) and ≥2 prescriptions for inhaled bronchodilators during 2008. Health care resource utilisation (HRU) outcomes during 2009 were assessed. Exacerbations were defined as: prescription for oral corticosteroids (OCS) in asthma and prescription of OCS or antibiotics in COPD; and/or hospitalisation for a respiratory cause.ResultsDual verification demonstrated consistency between SIR and Apollo data sources: 3453 (98.6%) patients were common to both systems; 99.9% of prescription records were matched and of 29,830 diagnosis records, one record was missing from Apollo and 272 (0.9%) from SIR. Identified COPD patients were also highly concordant (Kappa coefficient = 0.98).A total of 7981 asthma patients and 4478 COPD patients were identified within the NWEH-LDB. Cohort analyses enumerated the most commonly prescribed respiratory medication classes to be: inhaled corticosteroids (ICS) (42%) and ICS plus long-acting β2-agonist (LABA) (40%) in asthma; ICS plus LABA (55%) and long-acting muscarinic antagonists (36%) in COPD. During 2009 HRU was greater in the COPD versus asthma cohorts, and exacerbation rates in 2009 were higher in patients who had ≥2 exacerbations versus ≤1 exacerbation in 2008 for both asthma (137.5 vs. 20.3 per 100 person-years, respectively) and COPD (144.6 vs. 41.0, respectively).ConclusionApollo and SIR data extracts into NWEH-LDB showed a high level of concordance for asthma and COPD patients. Longitudinal data analysis characterized the COPD and asthma populations in Salford including medications prescribed and health care utilisation outcomes suitable for clinical trial planning.

Erratum: Type 2 inflammation in asthma — present in most, absent in many

Nature Reviews Immunology 15, 57–65 (2015) In the version of this article that was originally published, the targeted epitope of lebrikizumab was listed as "IL‑4Rα" in Table 1 but this should be "IL‑13 (IL‑4Rzα‑binding epitope)". Also, for the main effects of lebrikizumab in human asthma trials, thecitation of reference 44 should be reference 48.

Editorial introductions

Editorial introductions

Clinical asthma phenotyping: A trial for bridging gaps in asthma management.

Asthma is a common disease affecting millions of people worldwide and exerting an enormous strain on health resources in many countries. Evidence is increasing that asthma is unlikely to be a single disease but rather a series of complex, overlapping individual diseases or phenotypes, each defined by its unique interaction between genetic and environmental factors. Asthma phenotypes were initially focused on combinations of clinical characteristics, but they are now evolving to link pathophysiological mechanism to subtypes of asthma. Better characterization of those phenotypes is expected to be most useful for allocating asthma therapies. This article reviews different published researches in terms of unbiased approaches to phenotype asthma and emphasizes how the phenotyping exercise is an important step towards proper asthma treatment. It is structured into three sections; the heterogeneity of asthma, the impact of asthma heterogeneity on asthma management and different trials for phenotyping asthma.

Clinical trials to prevent/treat childhood asthma: methodologic issues

There is currently much excitement about clinical trials for the primary and secondary prevention of childhood asthma [1–3]. For the first time in over 40 years there are real novel therapeutic possibilities that deserve testing. In thinking about the design of these trials, it is critical to consider four issues: the traditional validity threats to clinical trials, how fetal lung development influences clinical trial design, how asthma natural history and asthma subphenotypes influence trial design and finally, drug dosing for these studies. As might be suspected, fetal lung development has its greatest impact on primary prevention trials and asthma sub phenotypes have its greatest effect on secondary prevention trials. Although people often focus on the randomized controlled nature of clinical trials, the methodological issues of blinding and randomization address internal validity, and not the source population from which trial subjects are drawn. The greatest validity threat to any clinical trial is the external validity generalizability of results, can the trial results be extrapolated to the population at large and what will be the population impact of the new treatment or preventative. Concrete examples of these generalizability issues can be seen in the source population for two of the new primary prevention trials in childhood asthma: the Vitamin D Antenatal Asthma Reduction Trial (VDAART) and the recent trial of vitamin C to prevent asthma in smoking pregnant women [1,2]. In the former case, VDAART is focused on women with a prior personal, or family, history of asthma, or allergies and giving them vitamin D to prevent asthma in their offspring. If successful, it will be a generalizability leap to all pregnant women, even those with a low genetic risk of asthma in their children, to extrapolate the trial results. In the latter case of vitamin C, the source, or target population, is the 12% of pregnant women who smoke and, as yet, there is no evidence that vitamin C will prevent asthma in nonsmoking pregnant women. This issue of generalizability is important in targeting public health interventions particularly in the area of primary prevention.

Rate of asthma trial outcomes reporting on ClinicalTrials.gov and in the published literature

Rate of asthma trial outcomes reporting on ClinicalTrials.gov and in the published literature

175: Interleukin-13 predisposes mice to more severe influenza infection by suppressing interferon responses and activating microRNA-21/PI3K

Rationale: Asthmatics and COPD patients are more susceptible to viral infections, which in turn are a major cause of exacerbations. However, the immunological mechanisms underpinning this association are largely unknown. Anti-interleukin (IL)-13 is currently in clinical trials for asthma, but the role of this cytokine in predispositing to viral infections is unknown. Methods: BALB/c mice were subjected to Ovalbumin (Ova)-, house dust mite (HDM)- or recombinant IL-13 (rIL-13)-induced models of allergic airway disease (AAD), or cigarette smoke-induced COPD, and infected with influenza virus (A/PR/8/34 strain). Some groups were treated with anti-IL-13 neutralizing antibody, miRNA-21-specific anatgomirs or PI3K inhibitors during influenza infection. The effects of infection on hallmark features of AAD (airway hyper-responsiveness [AHR], mucus secreting cell [MSC] numbers and eosinophil infiltration), COPD (lung function, inflammation) and on antiviral responses (viral load and interferon [IFN]-α, -β, -λ, -γ levels) were assessed. The cellular source of IL-13 was determined using novel IL-13 reporter mice. Results: Influenza infection increased the severity of Ova-, HDM- and rIL-13-induced AAD by increasing AHR, MSC numbers and lung eosinophils. Importantly, anti-IL-13 treatment during AAD returned AHR, MSC numbers and eosinophils back to control levels. Infection also exacerbated COPD. All models resulted in increased viral load, which correlated with suppressed IFN-α, -β, -λ, -γ and increased miR-21 and PI3K levels in the lung. Anti-IL-13 treatment also improved anti-viral responses leading to reduced viral load. IL-13 increased both miRNA-21 and PI3K. Inhibition of these molecules protected against infection. Influenza infection increased IL-13-production by NKT cells, ILC2s and Th2 cells. Conclusion: IL-13 responses during AAD and COPD lead to impaired antiviral immune responses resulting in more severe influenza infection that exacerbated the underlying disease. These studies identify anti-IL-13 and miRNA-21 and PI3K inhibitors as a potential therapies in influenza infections and influenza-induced exacerbations.

The Editor takes a closer look at some of this month's articles

The Editor takes a closer look at some of this month's articles